Development of a Selective CDK7 Covalent Inhibitor Reveals Predominant Cell-Cycle Phenotype

Calla M. Olson, Yanke Liang, Alan Leggett, Woojun D. Park, Lianbo Li, Caitlin E. Mills, Selma Z. Elsarrag, Scott B. Ficarro, Tinghu Zhang, Robert Düster, Matthias Geyer, Taebo Sim, Jarrod A. Marto, Peter K. Sorger, Ken D. Westover, Charles Y. Lin, Nicholas Kwiatkowski, Nathanael S. Gray

Research output: Contribution to journalArticlepeer-review

97 Citations (Scopus)


Cyclin-dependent kinase 7 (CDK7) regulates both cell cycle and transcription, but its precise role remains elusive. We previously described THZ1, a CDK7 inhibitor, which dramatically inhibits superenhancer-associated gene expression. However, potent CDK12/13 off-target activity obscured CDK7s contribution to this phenotype. Here, we describe the discovery of a highly selective covalent CDK7 inhibitor. YKL-5-124 causes arrest at the G1/S transition and inhibition of E2F-driven gene expression; these effects are rescued by a CDK7 mutant unable to covalently engage YKL-5-124, demonstrating on-target specificity. Unlike THZ1, treatment with YKL-5-124 resulted in no change to RNA polymerase II C-terminal domain phosphorylation; however, inhibition could be reconstituted by combining YKL-5-124 and THZ531, a selective CDK12/13 inhibitor, revealing potential redundancies in CDK control of gene transcription. These findings highlight the importance of CDK7/12/13 polypharmacology for anti-cancer activity of THZ1 and posit that selective inhibition of CDK7 may be useful for treatment of cancers marked by E2F misregulation. Olson et al. describe the development and characterization of YKL-5-124, a potent, selective, and covalent CDK7 inhibitor. YKL-5-124 displays biochemical and cellular selectivity for CDK7 over CDK12/13, structurally related kinases. CDK7 inhibition by YKL-5-124 induces a strong cell-cycle arrest and a surprisingly weak effect on RNA Pol II phosphorylation.

Original languageEnglish
Pages (from-to)792-803.e10
JournalCell Chemical Biology
Issue number6
Publication statusPublished - 2019 Jun 20

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Ltd


  • cancer
  • cell cycle
  • drug discovery
  • gene expression
  • small-molecule inhibitor
  • transcription

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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